Hemophilia A (HA) is an inherited bleeding disorder caused by mutations in the gene encoding clotting Factor VIII (FVIII). Because the gene is carried on the X chromosome, the disorder occurs almost exclusively in males with an incidence of approximately 1 in 5000 male births. Untreated, HA can result in uncontrolled bleeding resulting in death. Even if affected individuals survive bleeding episodes, bleeding into the joints can cause incapacitating joint damage, and spontaneous intracerebral bleeding can result in disabling neurological impairment.
Before the advent of FVIII replacement therapies, the disorder was highly lethal with most affected boys dying before the age of 20 from spontaneous bleeding or bleeding caused by trauma. After the discovery of plasma cryoprecipitate, containing FVIII and other clotting factors, and development of plasma-derived preparations of FVIII, the life expectancy and quality of life of HA patients improved dramatically. Although the number and severity of bleeding episodes was reduced by treatment with these products, viral contamination of the plasma supply with HIV and hepatitis viruses eventually caused devastating illnesses of their own. Eventually, the discovery of the FVIII gene and development of recombinantly produced FVIII preparations essentially eliminated the risk of viral contamination of FVIII replacement therapy.
Despite the availability of abundant supplies of recombinant FVIII for nearly two decades, replacement therapy for many HA patients remains sub-optimal. Due to the short half-life of FVIII (about 8-12 hours), severely affected HA patients require FVIII replacement every other day to maintain sufficient FVIII concentration to prophylactically prevent spontaneous bleeding. Although FVIII can be administered less frequently to stop bleeding caused by trauma, such on demand therapy is not effective to prevent spontaneous bleeding into the joints or brain which can also cause death or severe disability. Unfortunately, the frequent FVIII infusions required for prophylactic therapy is accompanied by its own problems. First, the therapy is very expensive. Second, it is associated with side effects such as septic arthritis. Third, it often requires placement of a central venous access device, which can be a source of infection and thrombosis. Fourth, patient compliance is difficult. And, fifth, frequent infusions of FVIII can cause development of antibody inhibitors to the clotting factor.
In light of the challenges associated with providing optimal prophylactic FVIII replacement therapy, there is a need in the art for ways of extending FVIII half-life after infusion. By increasing FVIII half-life, HA patients could administer the drug less frequently than is currently possible while maintaining sufficient FVIII concentration to prevent spontaneous bleeding.
Previous strategies to increase FVIII half-life have only achieved modest increases compared to wild type FVIII, but such improvements are not sufficient. Accordingly, there is a particular need in the art for new forms of FVIII having sufficiently long half-life that patients could maintain prophylaxis against spontaneous bleeding by administering the drug less frequently than is now possible.